1. Field of Invention
Novel 5-aminomethyl- and 5-hydroxymethyl-1-azabicyclo[3.2.1]octanes and 5-aminomethyl-and 5 -hydroxymethyl-1-azabicyclo[3.3.1]nonanes are coupled with aryl carboxylic acids to obtain the corresponding amides and esters. These novel amides and esters, their optical isomers, and their pharmaceutically acceptable salts are useful in increasing gastric motility, in preventing emesis including emesis caused by cytotoxic agents and radiation treatment associated with cancer therapy, in treating anxiety, and in controlling or modulating disorders attributed to serotonin imbalance such as cognitive dysfunction, migraine, or psychosis.
2. Information Disclosure Statement
A number of patents pertain to arylcarboxylic amides and esters of azabicyclic ring systems formed from amino- and hydroxy-azabicycloalkanes where the amino or hydroxy group is attached to a carbon other than a bridgehead carbon. For example, U.S. Pat. Nos. 4,593,034; 4,657,911 and 4,820,715 describe compounds having the formula below: ##STR2##
A German patent, German Offen. 2,748,260, describes azabicyclic amides of the formula: ##STR3## as having antiemetic and gastrokinetic utility. Class I antiarrhythmic compounds of the formula: ##STR4## where X is O or NH are disclosed in EP207514A2 (CA 106:1 56279r), JP 59/18417A2 (CA 102:45772a), JP 58/83694A2 (CA 99:122292m) and EP 39903A2 (CA 96:85419y). Unlike the compounds of the present invention these bridgehead substituted compounds have no intervening carbon between the bridgehead position and the ring nitrogen.
A European patent EP 094742A, and other subsequent patents, discloses compounds having the formula: ##STR5## where p=0-2, q=0-3, j=0-4, A is ArCONH and the benzamide NH and the ring nitrogen are separated by at least 2 carbon atoms. This generic formula broadly encompasses the compounds of the present invention. However, there are no claims made to any compound where the A-(CH.sub.2).sub.j - group is attached at the bridgehead position nor are there any examples or synthetic methods described which would support a bridgehead substitution. The intermediate azabicycloketones described preclude bridgehead substitution.
The arylcarboxylate amides and esters of the 5-aminomethyl- or 5-hydroxymethyl-1-azabicyclo[3.2.1]octanes or 1-azabicyclo[3.3.1]nonanes of this invention have not previously been described.